Kunert Jan-Philip, Müller Max, Günther Thomas, Stopper León, Urtz-Urban Nicole, Beck Roswitha, Wester Hans-Jürgen
Chair of Pharmaceutical Radiochemistry, Department of Chemistry, Technical University of Munich (TUM), Walther-Meißner-Str 3, 85748, Garching, Germany.
EJNMMI Res. 2023 Jan 16;13(1):2. doi: 10.1186/s13550-022-00942-7.
Radioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a Tc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa. However, commonly used [Tc]Tc-PSMA-I&S exhibits slow whole-body clearance, thus hampering optimal tumor-to-background ratios (TBR) during surgery. We therefore aimed to develop novel Tc-labeled, PSMA-targeted radioligands with optimized pharmacokinetic profile to increase TBR at the time of surgery.
Three Tc-labeled N4-PSMA ligands were preclinically evaluated and compared to [Tc]Tc-PSMA-I&S. PSMA affinity (IC) and internalization were determined on LNCaP cells. Lipophilicity was assessed by means of the distribution coefficient logD and an ultrafiltration method was used to determine binding to human plasma proteins. Biodistribution studies and static µSPECT/CT-imaging were performed at 6 h p.i. on LNCaP tumor-bearing CB17-SCID mice.
The novel N4-PSMA tracers were readily labeled with [Tc]TcO with RCP > 95%. Comparable and high PSMA affinity was observed for all [Tc]Tc-N4-PSMA-ligands. The ligands showed variable binding to human plasma and medium to low lipophilicity (logD - 2.6 to - 3.4), both consistently decreased compared to [Tc]Tc-PSMA-I&S. Biodistribution studies revealed comparable tumor uptake among all [Tc]Tc-N4-PSMA-ligands and [Tc]Tc-PSMA-I&S, while clearance from most organs was superior for the novel tracers. Accordingly, increased TBR were achieved. [Tc]Tc-N4-PSMA-12 showed higher TBR than [Tc]Tc-PSMA-I&S for blood and all evaluated tissue. In addition, a procedure suitable for routine clinical production of [Tc]Tc-N4-PSMA-12 was established. Labeling with 553 ± 187 MBq was achieved with RCP of 98.5 ± 0.6% (n = 10).
High tumor accumulation and favorable clearance from blood and non-target tissue make [Tc]Tc-N4-PSMA-12 an attractive tracer for RGS, possibly superior to currently established [Tc]Tc-PSMA-I&S. Its GMP-production according to a method presented here and first clinical investigations with this novel radioligand is highly recommended.
放射性引导手术（RGS）最近已成为复发性前列腺癌（PCa）治疗中一种有价值的新工具。术前注射锝标记的前列腺特异性膜抗原（PSMA）抑制剂后，借助合适的γ探测器可在放射性引导下术中识别和切除病变。初步临床经验表明RGS具有可行性，并提示其在复发性PCa中优于传统淋巴结清扫术。然而，常用的[锝]锝-PSMA-I&S全身清除缓慢，从而在手术期间妨碍了最佳的肿瘤与本底比值（TBR）。因此，我们旨在开发具有优化药代动力学特征的新型锝标记、靶向PSMA的放射性配体，以提高手术时的TBR。
对三种锝标记的N4-PSMA配体进行临床前评估，并与[锝]锝-PSMA-I&S进行比较。在LNCaP细胞上测定PSMA亲和力（IC）和内化。通过分配系数logD评估亲脂性，并使用超滤法测定与人血浆蛋白的结合。在注射后6小时对荷LNCaP肿瘤的CB17-SCID小鼠进行生物分布研究和静态μSPECT/CT成像。
新型N4-PSMA示踪剂易于用[锝]锝酸盐标记，放射性化学纯度（RCP）>95%。所有[锝]锝-N4-PSMA配体均观察到相当高的PSMA亲和力。这些配体与人血浆的结合各不相同，亲脂性为中等至低水平（logD为-2.6至-3.4），与[锝]锝-PSMA-I&S相比均持续降低。生物分布研究显示，所有[锝]锝-N4-PSMA配体和[锝]锝-PSMA-I&S的肿瘤摄取相当，而新型示踪剂从大多数器官的清除情况更好。因此，实现了TBR的提高。[锝]锝-N4-PSMA-12在血液和所有评估组织中的TBR均高于[锝]锝-PSMA-I&S。此外，还建立了一种适用于[锝]锝-N4-PSMA-12常规临床生产的方法。标记活度为553±187MBq，RCP为98.5±0.6%（n=10）。
高肿瘤蓄积以及从血液和非靶组织的良好清除，使[锝]锝-N4-PSMA-12成为RGS的一种有吸引力的示踪剂，可能优于目前已确立的[锝]锝-PSMA-I&S。强烈建议根据本文介绍的方法对其进行药品生产质量管理规范（GMP）生产，并对这种新型放射性配体进行首次临床研究。
